NEK1 haploinsufficiency worsens DNA damage, but not defective ciliogenesis, in C9ORF72 patient-derived iPSC-motoneurons.

The hexanucleotide G4C2 repeat expansion (HRE) in C9ORF72 gene is the major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to both loss- and gain-of-function pathomechanisms. The wide clinical heterogeneity among C9ORF72 patients suggests potential modifying genetic and epigenetic factors. Notably, C9ORF72 HRE often co-occurs with other rare variants in ALS/FTD-associated genes, such as NEK1, which encodes for a kinase involved in multiple cell pathways, including DNA damage response and ciliogenesis. In this study, we generated induced pluripotent stem cells (iPSCs) and differentiated motoneurons (iPSC-MNs) from an ALS patient carrying both C9ORF72 HRE and a NEK1 loss-of-function mutation to investigate the biological effect of NEK1 haploinsufficiency on C9ORF72 pathology in a condition of oligogenicity. Double mutant C9ORF72/NEK1 cells showed increased pathological C9ORF72 RNA foci in iPSCs and higher DNA damage levels in iPSC-MNs compared to single mutant C9ORF72 cells, but no effect on DNA damage response. When we analysed the primary cilium, we observed a defective ciliogenesis in C9ORF72 iPSC-MNs which was not worsened by NEK1 haploinsufficiency in the double mutant iPSC-MNs. Altogether, our study shows that NEK1 haploinsufficiency influences differently DNA damage and cilia length, potentially acting as a modifier at biological level in an in vitro ALS patient-derived disease model of C9ORF72 pathology.

De novo FRMD5 Missense Variants in Patients with Childhood-Onset Ataxia, Prominent Nystagmus, and Seizures.

BACKGROUND: FRMD5 variants were recently identified in patients with developmental delay, ataxia, and eye movement abnormalities. OBJECTIVES: We describe 2 patients presenting with childhood-onset ataxia, nystagmus, and seizures carrying pathogenic de novo FRMD5 variants. Weighted gene co-expression network analysis (WGCNA) was performed to gain insights into the function of FRMD5 in the brain. METHODS: Trio-based whole-exome sequencing was performed in both patients, and CoExp web tool was used to conduct WGCNA. RESULTS: Both patients presented with developmental delay, childhood-onset ataxia, nystagmus, and seizures. Previously unreported findings were diffuse choreoathetosis and dystonia of the hands (patient 1) and areas of abnormal magnetic resonance imaging signal in the white matter (patient 2). WGCNA showed that FRMD5 belongs to gene networks involved in neurodevelopment and oligodendrocyte function. CONCLUSIONS: We expanded the phenotype of FRMD5-related disease and shed light on its role in brain function and development. We recommend including FRMD5 in the genetic workup of childhood-onset ataxia and nystagmus. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cerebrospinal fluid and blood neurofilament light chain levels in amyotrophic lateral sclerosis and frontotemporal degeneration: A meta-analysis.

BACKGROUND AND PURPOSE: Neurofilament light chain (NFL) has been shown to be increased in amyotrophic lateral sclerosis (ALS) and, to a lesser extent, in frontotemporal dementia (FTD). A meta-analysis of NFL in ALS and FTD was performed. METHODS: Available studies comparing cerebrospinal fluid and blood NFL levels in ALS versus neurologically healthy controls (NHCs), other neurological diseases (ONDs) and ALS mimics, as well as in FTD and related entities (behavioural variant of FTD and frontotemporal lobar degeneration syndromes) versus NHCs, ONDs and other dementias were evaluated. RESULTS: In ALS, both cerebrospinal fluid and blood levels of NFL were higher compared to other categories. In FTD, behavioural variant of FTD and frontotemporal lobar degeneration syndromes, NFL levels were consistently higher compared to NHCs; however, several comparisons with ONDs and other dementias did not demonstrate significant differences. DISCUSSION: Amyotrophic lateral sclerosis is characterized by higher NFL levels compared to most other conditions. In contrast, NFL is not as good at discriminating FTD from other dementias.

Association of APOE genotype and cerebrospinal fluid Aß and tau biomarkers with cognitive and motor phenotype in amyotrophic lateral sclerosis.

OBJECTIVE: Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aß and tau proteins with cognitive and motor phenotype in ALS. METHODS: APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aß42, Aß40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype. RESULTS: APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aß42 (-0.8 vs. 0.1, log-transformed values) and Aß42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aß42 levels, possibly reflecting cerebral Aß deposition. While lower Aß42/40 correlated with lower memory score (ß = 0.20), Aß42 positively correlated with both ALS-specific (ß = 0.24) and ALS-nonspecific (ß = 0.24) scores. Although Aß42/40 negatively correlated with T-tau (ß = -0.29) and P-tau181 (ß = -0.33), we found an unexpected positive association of Aß42 and Aß40 with both tau proteins. Regarding motor phenotype, lower levels of Aß species were associated with lower motor neuron (LMN) signs (Aß40: ß = 0.34; Aß42: ß = 0.22). CONCLUSIONS: APOE haplotype and CSF Aß biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved.

European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).

BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS). METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available. RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management. CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.

The Single-Matrix Digit Cancellation Test, a Screener for Selective Attention Deficits: Standardization in an Italian Population Sample and Clinical Usability in Acute Stroke Patients.

INTRODUCTION: This study aimed at validating and providing Italian norms for the Single-Matrix Digit Cancellation Test (SMDCT), a cancellation task to screen for selective attention deficits, as well as providing clinical usability evidence for it in acute stroke patients. METHODS: The SMDCT stimulus is a specular, 4-quadrant, horizontally oriented matrix, across which target distribution is homogeneous. Both accuracy (-A) and time (-T) outcomes were computed. N = 263 healthy participants (HPs) and N = 76 acute stroke patients were recruited. N = 108 HPs also underwent the Mini-Mental State Examination, Frontal Assessment Battery (FAB), and Trail-Making Test (TMT), while patients were further assessed by the Mental Performance in Acute Stroke (MEPS). Regression-based norms were derived (equivalent scores). Construct and factorial validity, as well as case-control discrimination, were tested. RESULTS: The matrix was underpinned by a two-component structure reflecting left and right hits. The SMDCT-T and -A were associated with TMT and FAB scores, respectively. Education predicted the SMDCT-A/-T, whereas age predicted the SMDCT-T only. In patients, the SMDCT converged with the MEPS, also accurately discriminating them from HPs. An index of right-left difference differentiated right- from left-damaged patients. CONCLUSIONS: The SMDCT is a valid and normed screener for selective attention deficits, encompassing measures of both accuracy and time, whose adoption is encouraged in acute stroke patients. Relatedly, the horizontal disposition of its matrix does allow for the qualitative report of either leftward of rightward biases due to underlying visual or attentional-representational deficits in this population.

Duropathy as a rare motor neuron disease mimic: from bibrachial amyotrophy to infratentorial superficial siderosis.

BACKGROUND: Bibrachial amyotrophy associated with an extradural CSF collection and infratentorial superficial siderosis (SS) are rare conditions that may occasionally mimic ALS. Both disorders are assumed to be due to dural tears. CASE PRESENTATION: A 53-year-old man presented with a 7-year history of slowly progressive asymmetric bibrachial amyotrophy. Initially, a diagnosis of atypical motor neuron disease (MND) was made. At re-evaluation 11 years later, upper limb wasting and weakness had further progressed and were accompanied by sensorineural hearing loss. MRI of the brain and spine demonstrated extensive supra- and infratentorial SS (including the surface of the whole spinal cord) as well as a ventral longitudinal intraspinal fluid collection (VLISFC) extending along almost the entire thoracic spine. Osteodegenerative changes were observed at C5-C7 level, with osteophytes protruding posteriorly. The bony spurs at C6-C7 level were hypothesized to have lesioned the dura, causing a CSF leak and thus a VLISFC. Review of the MRI acquired at first evaluation showed that the VLISFC was already present at that time (actually beginning at C7 level), whereas the SS was not. 19 years after the onset of upper limb weakness, the patient additionally developed parkinsonism. Response to levodopa, brain scintigraphy with 123I-ioflupane and brain MRI with nigrosome 1 evaluation were consistent with idiopathic Parkinson's disease (PD). On the latest follow-up 21 years after symptom onset, the VLISFC was unchanged, as were upper arm weakness and wasting. CONCLUSIONS: Based on the long-term follow-up, we could establish that, while the evidence of the VLISFC was concomitant with the clinical presentation of upper limb amyotrophy and weakness, the radiological signs of SS appeared later. This suggests that SS was not per se the cause of the ALS-like clinical picture, but rather a long-term sequela of a dural leak. The latter was instead the causative lesion, giving rise to a VLISFC which compressed the cervical motor roots. Dural tears can actually cause several symptoms, and further studies are needed to elucidate the pathophysiological correlates of "duropathies". Finally, as iron metabolism has been implicated in PD, the co-occurrence of PD with SS deserves further investigation.

Further insights into anti-IgLON5 disease: a case with complex clinical presentation.

BACKGROUND: Anti-IgLON5 disease is an autoimmune encephalitis overlapping with neurodegenerative disorders due to pathological accumulation of hyperphosphorylated tau. It is characterized by several clinical manifestations determined by involvement of different brain areas, and mild response to first-line immunotherapies. We report a case of anti-IgLON5 disease with a multifaceted semiology and an unusually good response to glucocorticoid monotherapy. CASE PRESENTATION: A 68-year-old man with type 2 diabetes was evaluated for an 8-month history of progressive gait disorder causing frequent falls. He also suffered from obstructive sleep apneas and complained of dysphonia, dysarthria, occasional dysphagia, urinary incontinence, and upper limb action tremor. Neurological examination demonstrated bilateral eyelid ptosis, limitation of ocular horizontal smooth pursuit movements, slow horizontal saccades, and lack of inhibition of the vestibulo-ocular reflex during rapid horizontal head torsions. The patient also displayed involuntary, slow, rhythmic movements of the left periorbital and perioral muscles, spreading to the ipsilateral hemipalate and hemitongue, along with bilateral negative upper limb myoclonus. There were proximal muscle wasting in the upper limbs, proximal weakness of the four limbs, and diffuse fasciculations. Ataxia of stance and gait and of the four limbs was noted. MRI of the brain and spine was unremarkable; nerve conduction studies revealed a chronic, predominantly demyelinating, sensory-motor polyneuropathy, probably due to diabetes. Routine CSF examination was unrevealing and serum GFAP level was 89.6 pg/mL; however, the autoimmunity tests revealed a high-titer positivity for anti-IgLON5 autoantibodies in both CSF and serum, leading to the diagnosis of anti-IgLON5 disease. Symptoms improved significantly after intravenous methylprednisolone. CONCLUSIONS: Hemifacial and hemiorolingual myorhythmia along with peculiar oculomotor abnormalities characterizes the multifaceted clinical picture of our case. The complex semiology of our patient may reflect multifocal targeting of the autoimmune process or sequential spreading of tau inclusions in different brain areas. Our patient's optimal response to glucocorticoid monotherapy could be underpinned by a slightly different phenotype in which autoimmunity plays a greater pathogenic role than tauopathy, with a lower burden of tau deposition. In such patients, neurodegeneration and tau accumulation could be merely secondary to immune-mediated neuronal dysfunction, supporting the existence of a group of glucocorticoid-responsive patients.

Regional spreading pattern is associated with clinical phenotype in amyotrophic lateral sclerosis.

Increasing evidence shows that disease spreading in amyotrophic lateral sclerosis (ALS) follows a preferential pattern with more frequent involvement of contiguous regions from the site of symptom onset. The aim of our study was to assess if: (i) the burden of upper (UMN) and lower motor neuron (LMN) involvement influences directionality of disease spreading; (ii) specific patterns of disease progression are associated with motor and neuropsychological features of different ALS subtypes (classic, bulbar, primary lateral sclerosis, UMN-predominant, progressive muscular atrophy, flail arm, flail leg); and (iii) specific clinical features may help identify ALS subtypes, which remain localized to the site of onset for a prolonged time (regionally entrenching ALS). A single-centre, retrospective cohort of 913 Italian ALS patients was evaluated to assess correlations between directionality of the disease process after symptom onset and motor/neuropsychological phenotype. All patients underwent an extensive evaluation including the following clinical scales: Penn Upper Motor Neuron Score (PUMNS), MRC Scale for Muscle Strength and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The most frequent initial spreading pattern was that towards adjacent horizontal regions (77.3%), which occurred preferentially in patients with lower MRC scores (P = 0.038), while vertical diffusion (21.1%) was associated with higher PUMNS (P < 0.001) and with reduced survival (P < 0.001). Non-contiguous disease spreading was associated with more severe UMN impairment (P = 0.003), while contiguous disease pattern with lower MRC scores. Furthermore, non-contiguous disease spreading was associated with more severe cognitive impairment in both executive and visuospatial ECAS domains. Individuals with regionally entrenching ALS were more frequently female (45.6% versus 36.9%; P = 0.028) and had higher frequencies of symmetric disease onset (40.3% versus 19.7%; P < 0.001) and bulbar phenotype (38.5% versus 16.4%; P < 0.001). Our study suggests that motor phenotypes characterized by a predominant UMN involvement are associated with a vertical pattern of disease progression reflecting ipsilateral spreading within the motor cortex, while those with predominant LMN involvement display more frequently a horizontal spreading from one side of the spinal cord to the other. These observations raise the hypothesis that one of the mechanisms underlying disease spreading in ALS pathology is represented by diffusion of toxic factors in the neuron microenvironment. Finally, it is possible that in our cohort, regionally entrenching ALS forms are mainly observed in patients with atypical bulbar phenotypes, characterized by a slowly progressive course and relatively benign prognosis.

Genetic variability in sporadic amyotrophic lateral sclerosis.

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS.

Emotional awareness in patients with amyotrophic lateral sclerosis.

INTRODUCTION: It has been recently acknowledged that deficits in experiencing and processing one's own emotions, also termed alexithymia, may possibly feature the frontotemporal-spectrum disorders. This study aims to determine whether alexithymia could be included within the frontotemporal syndromes of amyotrophic lateral sclerosis (ALS). METHODS: Alexithymic traits were estimated in a cohort of 68 non-demented ALS patients with the 20-item Toronto Alexithymia Scale (TAS-20). Patients were assessed for the identification of motor-phenotypes and frontotemporal syndromes based on current classification criteria. Spearman's coefficients explored the correlates of TAS-20 measures with motor-functional profiles, global cognitive, social-cognitive (emotion recognition and empathy) and behavioral status. RESULTS: Abnormal TAS-20 scores were found in 13% of patients, and their distribution did not vary within motor and frontotemporal phenotypes. Significant associations were detected between TAS-20 and executive (p ≤ .011), memory (p = .006), state-anxiety (p ≤ .013) and depression measures (p ≤ .010). By contrast, TAS-20 scores were unrelated to social-cognitive performances, dysexecutive and apathetic profiles. Disease duration was the only motor-functional feature being related to the TAS-20 (p ≤ .008). CONCLUSIONS: Alexithymia of potential clinical relevance occur in a minority of ALS patients, and its neuropsychological correlates mostly resemble those featuring the general population. Hence, it is unlikely that alexithymia is a specific feature of frontotemporal-spectrum characterizing ALS, rather it could be an expression of psychogenic factors as a reaction to the disease.

Frontotemporal-spectrum disorders and functional independence in non-demented ALS patients.

BACKGROUND: The present study aimed at determining whether, net of motor confounders, neuropsychological features affect functional independence (FI) in activities of daily living (ADLs) in non-demented amyotrophic lateral sclerosis (ALS) patients. METHODS: N = 88 ALS patients without frontotemporal dementia were assessed for FI-Katz's Basic ADL Scale (BADL) and Lawton-Brody's Instrumental ADL Scale (IADL)-, cognition-Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-Beaumont Behavioural Inventory and Dimensional Apathy Scale. The association between cognitive and behavioural measures and BADL/IADL scores was assessed by covarying for demographics, anxiety and depression levels, disease duration and motor confounders-i.e. ALS Functional Rating Scale-Revised (ALSFRS-R) scores, progression rate and both King's and Milano-Torino stages. RESULTS: Higher scores on the ECAS-Language were associated with higher IADL scores (p = 0.005), whilst higher apathetic features-as measured by the Dimensional Apathy Scale (DAS)-were inversely related to the BADL (p = 0.003). Whilst IADL scores were related to all ECAS-Language tasks, the DAS-Initiation was the only subscale associated with BADL scores. Patients with abnormal ECAS-Language (p = 0.023) and DAS (p = 0.008) scores were more functionally dependent than those without. DISCUSSION: Among non-motor features, language changes and apathetic features detrimentally affect FI in non-demented ALS patients.

Ecological validity of performance-based cognitive screeners in amyotrophic lateral sclerosis: preliminary evidence.

BACKGROUND: This study aimed at preliminarily assessing, in a cohort of non-demented amyotrophic lateral sclerosis (ALS) patients, the ecological validity, and more specifically the veridicality, of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioral Screen (ALS-CBS™), by relating their scores to caregiver-report ratings of cognitive changes. METHODS: N = 147 patient-caregiver dyads were recruited. Patients were administered the ECAS and ALS-CBS™, whilst caregiver the Caregiver Behavioral Questionnaire (CBQ) and Beaumont Behavioural Inventory (BBI). An Ecological Cognitive Functioning Index (ECFI) was derived from those items of the CBQ and BBI that tap on executive and language changes. Ecological validity was assessed via both correlational and predictive analyses net of caregiver-rated behavioural changes (as assessed by the ECAS-Carer Interview). RESULTS: The ECFI was associated with the total scores on both the ECAS (p = .014) and ALS-CBS™ (p = .017). When looking at ECAS and ALS-CBS™ subscales, those assessing verbal fluency were selectively associated with the ECFI. The ECFI was higher in patients performing defectively on the ECAS (p = .004) and on the ALS-CBS™ (p = .027). DISCUSSION: This study suggests that both the ECAS and the ALS-CBS™ represent a valid estimate of non-demented ALS patients' cognitive status in the real world, also highlighting the clinical relevance of cognitive changes reported by caregivers.

Psychometrics and diagnostics of the Italian version of the Alternate Verbal Fluency Battery (AVFB) in non-demented Parkinson's disease patients.

BACKGROUND: Verbal fluency (VF) tasks are known as suitable for detecting cognitive impairment (CI) in Parkinson's disease (PD). This study thus aimed to evaluate the psychometrics and diagnostics of the Alternate Verbal Fluency Battery (AVFB) by Costa et al. (2014) in an Italian cohort of non-demented PD patients, as well as to derive disease-specific cut-offs for it. METHODS: N = 192 non-demented PD patients were screened with the Montreal Cognitive Assessment (MoCA) and underwent the AVFB-which includes phonemic, semantic and alternate VF tests (PVF; SVF; AVF), as well as a Composite Shifting Index (CSI) reflecting the "cost" of shifting from a single- to a double-cued VF task. Construct validity and diagnostics were assessed for each AVFB measure against the MoCA. Internal reliability and factorial validity were also tested. RESULTS: The MoCA proved to be strongly associated with PVF, SVF and AVF scores, whilst moderately with the CSI. The AVFB was internally consistent and underpinned by a single component; however, an improvement in both internal reliability and fit to its factorial structure was observed when dropping the CSI. Demographically adjusted scores on PVF, SVF and AVF tests were diagnostically sound in detecting MoCA-defined cognitive impairment, whilst this was not true for the CSI. Disease-specific cut-offs for PVF, SVF and AVF tests were derived. DISCUSSION: In conclusion, PVF, SVF and AVF tests are reliable, valid and diagnostically sound instruments to detect cognitive impairment in non-demented PD patients and are therefore recommended for use in clinical practice and research.

Validity, diagnostics and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in Huntington's disease.

BACKGROUND: This study is aimed at assessing the clinimetric properties and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in patients with Huntington's disease (HD). METHODS: N = 39 motor-manifest HD patients, N = 74 Parkinson's disease (PD) patients and N = 92 matched HCs were administered the MoCA. HD patients further underwent the Unified Huntington's Disease Rating Scale (UHDRS), self-report questionnaires for anxiety and depression and a battery of first- and second-level cognitive tests. Construct validity was tested against cognitive and behavioural/psychiatric measures, whereas ecological validity against motor-functional subscales of the UHDRS. Sensitivity to disease severity was tested, via a logistic regression, by exploring whether the MoCA discriminated between patients in Shoulson-Fahn stage ≤ 2 vs. > 2. The same analysis was employed to test its ability to discriminate HD patients from HCs and PD patients. RESULTS: The MoCA converged towards cognitive and behavioural measures but diverged from psychiatric ones, being also associated with motor/functional measures from the UHDRS. In identifying patients with cognitive impairment, adjusted MoCA scores were highly accurate (AUC = .92), yielding optimal diagnostics at the cut-off of < 19.945 (J = .78). The MoCA was able to discriminate patients in the middle-to-advanced from those in the early-to-middle stages of the disease (p = .037), as well as to differentiate HD patients from both HCs (p < .001) and PD patients (p < .001). CONCLUSIONS: The MoCA is a valid, diagnostically sound and feasible cognitive screener in motor-manifest HD patients, whose adoption is thus encouraged in clinical practice and research.

Longitudinal Feasibility of the Montreal Cognitive Assessment (MoCA) in Non-Demented ALS Patients.

INTRODUCTION: The present study aimed at testing the longitudinal feasibility of the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented amyotrophic lateral sclerosis (ALS) patients. METHODS: N = 39 non-demented ALS patients were followed-up at a 5-to-10-month interval (M = 6.8; SD = 1.4) with the MoCA and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Practice effects, test-retest reliability, and predictive validity (against follow-up ECAS scores) were assessed. Reliable change indices (RCIs) were derived via a regression-based approach by accounting for retest interval and baseline confounders (i.e., demographics, disease duration, and severity and progression rate). RESULTS: At retest, 100% and 69.2% of patients completed the ECAS and the MoCA, respectively. Patients who could not complete the MoCA showed a slightly more severe and fast-progressing disease. The MoCA was not subject to practice effects (t[32] = -0.80; p = 0.429) and was reliable at retest (intra-class correlation = 0.82). Moreover, baseline MoCA scores predicted the ECAS at retest. RCIs were successfully derived - with baseline MoCA scores being the only significant predictor of retest performances (ps < 0.001). CONCLUSIONS: As long as motor disabilities do not undermine its applicability, the MoCA appears to be longitudinally feasible at a 5-to-10-month interval in non-demented ALS patients. However, ALS-specific screeners - such as the ECAS - should be preferred whenever possible.

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases.

Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions. We used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease. We found no evidence for enrichment of positively-selected SNPs in the heritability of Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease, suggesting that common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk. These findings provide insight into the origins of neurodegenerative disorders within the evolution of Homo sapiens and addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.

Resting state functional brain networks associated with emotion processing in frontotemporal lobar degeneration.

This study investigated the relationship between emotion processing and resting-state functional connectivity (rs-FC) of the brain networks in frontotemporal lobar degeneration (FTLD). Eighty FTLD patients (including cases with behavioral variant of frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy syndrome, motor neuron disease) and 65 healthy controls underwent rs-functional MRI. Emotion processing was tested using the Comprehensive Affect Testing System (CATS). In patients and controls, correlations were investigated between each emotion construct and rs-FC changes within critical networks. Mean rs-FC of the clusters significantly associated with CATS scoring were compared among FTLD groups. FTLD patients had pathological CATS scores compared with controls. In controls, increased rs-FC of the cerebellar and visuo-associative networks correlated with better scores in emotion-matching and discrimination tasks, respectively; while decreased rs-FC of the visuo-spatial network was related with better performance in the affect-matching and naming. In FTLD, the associations between rs-FC and CATS scores involved more brain regions, such as orbitofrontal and middle frontal gyri within anterior networks (i.e., salience and default-mode), parietal and somatosensory regions within visuo-spatial and sensorimotor networks, caudate and thalamus within basal-ganglia network. Rs-FC changes associated with CATS were similar among all FTLD groups. In FTLD compared to controls, the pattern of rs-FC associated with emotional processing involves a larger number of brain regions, likely due to functional specificity loss and compensatory attempts. These associations were similar across all FTLD groups, suggesting a common physiopathological mechanism of emotion processing breakdown, regardless the clinical presentation and pattern of atrophy.

Clinimetrics of the Italian version of the Montreal Cognitive Assessment (MoCA) in adult-onset idiopathic focal dystonia.

This study aimed at assessing the clinimetrics of the Montreal Cognitive Assessment (MoCA) in an Italian cohort of patients with adult-onset idiopathic focal dystonia (AOIFD). N = 86 AOIFD patients and N = 92 healthy controls (HCs) were administered the MoCA. Patients further underwent the Trail-Making Test (TMT) and Babcock Memory Test (BMT), being also screened via the Beck Depression Inventory-II (BDI-II) and the Dimensional Apathy Scale (DAS). Factorial structure and internal consistency were assessed. Construct validity was tested against TMT, BMT, BDI-II and DAS scores, whilst diagnostics against the co-occurrence of a defective performance on at least one TMT measure and on the BMT. Case-control discrimination was examined. The association between MoCA scores and motor-functional measures was explored. The MoCA was underpinned by a mono-component structure and acceptably reliable at an internal level. It converged towards TMT and BMT scores, as well as with the DAS, whilst diverging from the BDI-II. Its adjusted scores accurately detected cognitive impairment (AUC = .86) at a cut-off of < 17.212. The MoCA discriminated patients from HCs (p < .001). Finally, it was unrelated to disease duration and severity, as well as to motor phenotypes. The Italian MoCA is a valid, diagnostically sound and feasible cognitive screener in AOIFD patients.

Clinimetrics and feasibility of the Italian version of the Frontal Assessment Battery (FAB) in non-demented Parkinson's disease patients.

BACKGROUND: This study aimed at assessing the cross-sectional and longitudinal clinimetrics and feasibility of the Frontal Assessment Battery (FAB) in non-demented Parkinson's disease (PD) patients. METHODS: N = 109 PD patients underwent the FAB and the Montreal Cognitive Assessment (MoCA). A subsample of patients further underwent a thorough motor, functional and behavioral evaluation (the last including measures of anxiety, depression and apathy). A further subsample was administered a second-level cognitive battery tapping on attention, executive functioning, language, memory, praxis and visuo-spatial abilities. The following properties of the FAB were tested: (1) concurrent validity and diagnostics against the MoCA; (2) convergent validity against the second-level cognitive battery; (4) association with motor, functional and behavioral measures; (5) capability to discriminate patients from healthy controls (HCs; N = 96); (6) assessing its test-retest reliability, susceptibility to practice effects and predictive validity against the MoCA, as well as deriving reliable change indices (RCIs) for it, at a ≈ 6-month interval, within a subsample of patients (N = 33). RESULTS: The FAB predicted MoCA scores at both T0 and T1, converged with the vast majority of second-level cognitive measures and was associated with functional independence and apathy. It accurately identified cognitive impairment (i.e., a below-cut-off MoCA score) in patients, also discriminating patients from HCs. The FAB was reliable at retest and free of practice effects; RCIs were derived according to a standardized regression-based approach. DISCUSSION: The FAB is a clinimetrically sound and feasible screener for detecting dysexecutive-based cognitive impairment in non-demented PD patients.